Growth hormone induces somatostatin and insulin-like growth factor I gene expression in the cerebral hemispheres of aging rats.

Abstract

The neuropeptide somatostatin (SS) plays a role as a modulator of cognitive functions and as a potential tropic factor in the central nervous system. A reduction in SS levels has been demonstrated in the aging brain and in dementia. In addition, insulin-like growth factor I (IGF-I) acts as a paracrine factor in multiple GH actions and is also found in the cerebral hemispheres, where it exerts neurotropic effects. We used aging rats as an in vivo model of GH deficiency to study the possible participation of exogenous GH in the modulation of the cerebral hemispheric SS and IGF-I. Two sets of experiments were carried out. In the first set, the age-related patterns of GH, IGF-I, and SS in the serum, pituitary, and cerebral hemispheres were established. In the second experimental set, 90-day-old (adult) and 2-yr-old (aging) male rats received recombinant human GH (200 micrograms/ sc-day) or vehicle for 7 consecutive days. The serum levels of rat GH and IGF-I as well as pituitary GH messenger RNA decreased in 2-yr-old rats compared with those in adult rats. After GH treatment, pituitary GH messenger RNA levels decreased markedly in the 90-day-old and 2-yr-old rats. Serum immunoreactive GH decreased in the adult animals, whereas it remained unaffected in the aging ones, whereas serum IGF-I levels were not altered by GH treatment in either group. Immunoreactive levels and messenger RNA of both SS and IGF-I were low in the cerebral hemispheres of aging rats, but were restored to the levels found in adult rats after GH treatment. As treatment did not induce changes in the serum IGF-I levels, these results provide evidence of a stimulatory action of peripherally administered GH on the regulation of SS and IGF-I genes in the aging rat in the central nervous system. These data also show a new target action for GH and could provide a molecular basis for the improvement of some symptoms of GH deficiency that occurs after recombinant human GH treatment.

Sensitivity to exogenous GH and reversibility of the reduced IGF-I gene expression in aging rats

“…The effect observed of exogenous rhGH administration on serum and pituitary IR-GH and the action on the accumulation of GH mRNA confirms previous studies showing that GH regulates its own secretion throughout a negative long-loop feedback mechanism inhibiting GH release and gene expression in the pituitary (40,49). The relative sensitivity of this negative feedback action can be concluded from the fact that exogenous GH is given at the same dose per body weight in the middle-aged and old rats.…”

“…However, in partially deficient rats, specific doses and frequency of GH administration are required to make this effect evident. In fact, it was not observed when one dose of 200 mg/day was given to 24-month-old normal rats for 7 days (40). In this study we have been able to show a complete reversion of the liver IGF-I mRNA to the levels of young adult rats, by giving 150 mg every 12 h by s.c. route for 7 days to 27-month-old normal animals.…”

Peripheral administration of GH induces cell proliferation in the brain of adult hypophysectomized rats

“…Although it is clear that this process actually may occur (Lopezfernandez et al 1996), it is more controversial to what extent in various brain regions it is active (Frago et al 2002). In our in vivo experiments we cannot discriminate between the possibilites of GH acting via increasing local brain IGF-I or by acting solely on its own.…”

Different modes of GH administration influence gene expression in the male rat brain

“…the BBB. Although it is now accepted that GH does cross the BBB (Lopez-Fernandez et al 1996, Ye et al 1997) at a limited rate (Pan et al 2005), it is clear that a pulsatile effect of GH injections may be attenuated by a limited and delayed passage of GH. Secondly the effect of GH in the brain may be delayed due to peripheral GH stimulation of local IGF1 expression within the brain (Ye et al 1997).…”

“…Importantly, GH administration also exerts neuroprotective (Gustafson et al 1999, Scheepens et al 2001, Pathipati et al 2009) and cell-proliferative effects (Å berg et al 2009, 2010). The fact that GH-receptors are expressed in both glial cells and neurons (Lobie et al 1993) and that GH crosses the blood-brain barrier (BBB) (Lopez-Fernandez et al 1996, Ye et al 1997 indicates that circulating GH can stimulate both cell types directly.…”